Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease characterized by an increased left ventricular mass in the absence of another cause for hypertrophy. This disease provides a model to study the process of cardiac hypertrophy. In approximately 15% of affected families, the disease gene encodes a beta myosin heavy chain (BMHC) gene with a missense mutation. We have identified 32 distinct mutations in the BMHC gene and mapped them onto the 3D structure of the head of skeletal myosin. The mutations cluster in 4 regions, suggesting different types of interference in the actomyosin cross-bridge kinetics as a function of mutation location. We have studied the mechanical properties of extracted mutant myosins and muscle fibers expressing these myosins, to analyze the pathophysiology at a molecular level. One of the clusters of mutations led us to the discovery of mutations in the myosin light chains which cause a variant of HCM characterized by an obstruction in the middle of the left ventricle. Through a series of arguments, the association of the myosin light chain mutations with the rare subtype of HCM led us to hypothesize the importance of the stretch-activation response to the function of the normal heart. The stretch-activation response in Drosophila flight muscle has been previously shown to be distorted by a mutation in the regulatory myosin light chain (RLC), resulting in flightless flies whose wings do not beat properly. We have developed transgenic mice expressing the mutant myosin essential light chain (ELC), from a patient with cardiac hypertrophy. The hearts from these mice also do not beat properly. That is, there is a shift of the frequency of maximum power output to a rate beyond the physiologic range, with consequent loss of oscillatory power. We have cloned the human enzyme that phosphorylates the RLC and identified naturally occurring variations of the human phosphorylating enzyme in the African-American population that we will study in a hypertensive population. To study this effect in an animal model, we have overexpressed the enzyme in mice. Muscle fibers from these mice and others we have produced, are being used to study the basic biophysical response of muscle fibers to light chain phosphorylation. An antibody to the phosphorylated site has been produced and processed to provide a first approximation to a therapeutic intervention in isolated muscle fibers from these mice. We are also using these mice to study what we believe are cardiac muscle stem cells produced in these mice. - hypertrophic cardiomyopathy (HCM), beta myosin heavy chain (BMHC)gene - Human Subjects & Human Subjects: Interview, Questionaires, or Surveys Only